Novel 2-Azetidinone Derivatives And Their Use As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemia

ABSTRACT

Compounds of formula (I) (wherein variable groups are as defined within) pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia are described. Processes for their manufacture and pharmaceutical compositions containing them are also described.

This invention relates to 2-azetidinone derivatives, or pharmaceuticallyacceptable salts, solvates, solvates of such salts and prodrugs thereof.These 2-azetidinones possess cholesterol absorption inhibitory activityand are accordingly of value in the treatment of disease statesassociated with hyperlipidaemic conditions. They are therefore useful inmethods of treatment of a warm-blooded animal, such as man. Theinvention also relates to processes for the manufacture of said2-azetidinone derivatives, to pharmaceutical compositions containingthem and to their use in the manufacture of medicaments to inhibitcholesterol absorption in a warm-blooded animal, such as man. A furtheraspect of this invention relates to the use of the compounds of theinvention in the treatment of dyslipidemic conditions.

Atherosclerotic coronary artery disease is a major cause of death andmorbidity in the western world as well as a significant drain onhealthcare resources. It is well-known that hyperlipidaemic conditionsassociated with elevated concentrations of total cholesterol and lowdensity lipoprotein (LDL) cholesterol are major risk factors forcardiovascular atherosclerotic disease (for instance “Coronary HeartDisease: Reducing the Risk; a Worldwide View” Assman G., Carmena R.Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes andCardiovascular Disease: A Statement for Healthcare Professionals fromthe American Heart Association” Grundy S, Benjamin I., Burke G., et al;Circulation, 1999, 100, 1134-46).

The concentration of plasma cholesterol depends on the integratedbalance of endogenous and exogenous pathways of cholesterol metabolism.In the endogenous pathway, cholesterol is synthesized by the liver andextra hepatic tissues and enters the circulation as lipoproteins or issecreted into bile. In the exogenous pathway cholesterol from dietaryand biliary sources is absorbed in the intestine and enters thecirculation as component of chylomicrons. Alteration of either pathwaywill affect the plasma concentration of cholesterol.

The precise mechanism by which cholesterol is absorbed from theintestine is however not clear. The original hypothesis has been thatcholesterol is crossing the intestine by unspecific diffusion. But morerecent studies are suggesting that there are specific transportersinvolved in the intestinal cholesterol absorption. (See for instance Newmolecular targets for cholesterol-lowering therapy Izzat, N. N.,Deshazer, M. E. and Loose-Mitchell D. S. JPET 293:315-320, 2000.)

A clear association between reduction of total cholesterol and (LDL)cholesterol and decreased instance of coronary artery disease has beenestablished, and several classes of pharmaceutical agents are used tocontrol serum cholesterol. There major options to regulate plasmacholesterol include (i) blocking the synthesis of cholesterol by agentssuch as HMG-CoA reductase inhibitors, for example statins such assimvastatin and fluvastatin, which also by up-regulation ofLDL-receptors will promote the cholesterol removal from the plasma; (ii)blocking the bile acid reabsorption by specific agents resulting inincreased bile acid excretion and synthesis of bile acids fromcholesterol with agents such as bile acid binders, such as resins e.g.cholestyramine and cholestipol; and (iii) by blocking the intestinaluptake of cholesterol by selective cholesterol absorption inhibitors.High density lipoprotein (HDL) elevating agents such as fibrates andnicotinic acid analogues have also been employed.

Even with the current diverse range of therapeutic agents, a significantproportion of the hypercholesterolaemic population is unable to reachtarget cholesterol levels, or drug interactions or drug safety precludethe long term use needed to reach the target levels. Therefore there isstill a need to develop additional agents that are more efficacious andare better tolerated.

Compounds possessing such cholesterol absorption inhibitory activityhave been described, see for instance the compounds described in WO93/02048, WO 94/17038, WO 95/08532, WO 95/26334, WO 95/35277, WO96/16037, WO 96/19450, WO 97/16455, WO 02/50027, WO 02/50060, WO02/50068, WO 02/50090, WO 02/66464, WO 04/000803, WO 04/000804,WO04/000805, U.S. Pat. No. 5,756,470, U.S. Pat. No. 5,767,115 and U.S.RE37721.

The present invention is based on the discovery that certain2-azetidinone derivatives surprisingly inhibit cholesterol absorption.Such properties are expected to be of value in the treatment of diseasestates associated with hyperlipidaemic conditions. The compounds of thepresent invention are not disclosed in any of the above applications andwe have surprisingly found that the compounds of the present inventionpossess beneficial efficacious, metabolic and toxicological profilesthat make them particularly suitable for in vivo administration to awarm blooded animal, such as man. In particular certain compounds of thepresent invention have a low degree of absorption compared to compoundsof the prior art whilst retaining their ability to inhibit cholesterolabsorption.

Accordingly there is provided a single diastereomeric compound offormula (I):

wherein:

R¹ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein saidC₁₋₆alkyl may be optionally substituted by one or more hydroxy, amino,guanidino, carbamoyl, carboxy, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁-C₆ alkylcarbonylamino C₁₋₆alkylS(O)_(a)wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and wherein any aryl group maybe optionally substituted by one or two substituents selected from halo,hydroxy, C₁₋₆alkyl or C₁₋₆alkoxy;

R² is hydrogen, a branched or unbranched C₁₋₆alkyl, C₃₋₆cycloalkyl oraryl; wherein said C₁₋₆alkyl may be optionally substituted by one ormore hydroxy, amino, guanidino, carbamoyl, carboxy, C₁₋₆alkoxy, (C₁-C₄alkyl)₃Si, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a)wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and wherein any aryl group maybe optionally substituted by one or two substituents selected from halo,hydroxy, C₁₋₆alkyl or C₁₋₆alkoxy;R³ is hydrogen, alkyl, halo or C₁₋₆alkoxy;R⁴ is hydrogen, halo or C₁₋₆alkoxy;R⁵ is hydrogen, C₁₋₆ alkyl, arylalkyl, or arylC₁₋₆ alkyl;R⁶ is hydrogen, C₁₋₆ alkyl, or arylC₁₋₆alkyl;wherein R⁵ and R² may form a ring with 2-7 carbon atoms and wherein R⁶and R² may form a ring with 3-6 carbon atoms;or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In one aspect of the invention R¹ is hydrogen. According to anotheraspect of the invention, R² is hydrogen, a branched or unbranchedC₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein said C₁₋₆alkyl may beoptionally substituted by one or more hydroxy, amino, C₁₋₆alkylS(O)_(a)wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and wherein any aryl group maybe optionally substituted by hydroxy. According to a further aspect ofthe invention, R³ is hydrogen, methoxy, or an alkyl, for instancemethyl, or a halogen, for instance chlorine or fluorine. According toyet another aspect of the invention R⁴ is halo, chlorine or fluorine.According to a further aspect of the invention, R⁶ is hydrogen, arylC₁₋₆or R⁶ and R² form a ring with 3-6 carbon atoms.

According to one aspect of the invention R¹ is hydrogen, R² is abranched or unbranched C₁₋₄alkyl, optionally substituted by aC₃₋₆cycloalkyl or an amino, R³ and R⁴ are halo, R⁵ is hydrogen or C₁₋₆alkyl, and R⁶ is hydrogen.

The invention further provides for one or more compounds chosen from:

-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or    S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valine;-   1-[(N-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[(2R or    S)-2-(4-chlorophenyl)-2-hydroxyethyl]thio-}4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]cyclopropanecarboxylic    acid;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or    S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-methyl-D-valine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or    S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-cyclohexyl-D-alanine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or    S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-β,β-dimethyl-D-phenylalanine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or    S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine.

According to an embodiment of the invention it is provided for one ormore compounds chosen from:

-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valine;-   1-[(N-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]cyclopropanecarboxylic    acid;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-methyl-D-valine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-cyclohexyl-D-alanine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-β,β-dimethyl-D-phenylalanine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine.

According to an embodiment of the invention it is provided for one ormore compounds chosen from:

-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valine;-   1-[(N-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]cyclopropanecarboxylic    acid;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-methyl-D-valine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-cyclohexyl-D-alanine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-β,β-dimethyl-D-phenylalanine;-   N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” and “C₁₋₄alkyl” include propyl, isopropyl andt-butyl. However, references to individual alkyl groups such as ‘propyl’are specific for the straight chained version only and references toindividual branched chain alkyl groups such as ‘isopropyl’ are specificfor the branched chain version only. A similar convention applies toother radicals, for example “phenylC₁₋₆alkyl” would include benzyl,1-phenylethyl and 2-phenylethyl. The term “halo” refers to fluoro,chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

The term “aryl” refers to a 4-10 membered aromatic mono or bicyclic ringcontaining 0 to 5 heteroatoms independently selected from nitrogen,oxygen or sulphur. Examples of aryls include phenyl, pyrrolyl, furanyl,imidazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyridyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl,thiazolyl, 1,2,4-triazolyl, thienyl, naphthyl, benzofuranyl,benzimidazolyl, benzthienyl, benzthiazolyl, benzisothiazolyl,benzoxazolyl, benzisoxazolyl, 1,3-benzodioxolyl, indolyl,pyridoimidazolyl, pyrimidoimidazolyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl and naphthyridinyl.Particularly “aryl” refers to phenyl, thienyl, pyridyl, imidazolyl orindolyl.

Examples of “C₁₋₆alkoxy” include methoxy, ethoxy and propoxy. Examplesof “C₁₋₆alkylS(O)_(a) wherein a is 0 to 2” include methylthio,ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.Examples of “N—(C₁₋₆alkyl)amino” include methylamino and ethylamino.Examples of “N,N—(C₁₋₆alkyl)₂amino” include di-N-methylamino,di-(N-ethyl)amino and N-ethyl-N-methylamino. “C₃₋₆cycloalkyl” refers tocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

A suitable pharmaceutically acceptable salt of a compound of theinvention, or other compounds disclosed herein, is, for example, anacid-addition salt of a compound of the invention which is sufficientlybasic, for example, an acid-addition salt with, for example, aninorganic or organic acid, for example hydrochloric, hydrobromic,sulphuric, phosphoric, trifluoroacetic, citric, acetate or maleic acid.In addition a suitable pharmaceutically acceptable salt of a compound ofthe invention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically-acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The compounds of the formula (I), or other compounds disclosed herein,may be administered in the form of a pro-drug which is broken down inthe human or animal body to give a compound of the formula (I). examplesof pro-drugs include in vivo hydrolysable esters and in vivohydrolysable amides of a compound of the formula (I).

An in vivo hydrolysable ester of a compound of the formula (I), or othercompounds disclosed herein, containing carboxy or hydroxy group is, forexample, a pharmaceutically acceptable ester which is hydrolysed in thehuman or animal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include C₁₋₆alkoxymethylesters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters forexample pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I), or othercompounds disclosed herein, containing a hydroxy group includesinorganic esters such as phosphate esters and α-acyloxyalkyl ethers andrelated compounds which as a result of the in vivo hydrolysis of theester breakdown to give the parent hydroxy group. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an in vivo hydrolysable amide of a compound of theformula (I), or other compounds disclosed herein, containing a carboxygroup is, for example, a N—C₁₋₆alkyl or N,N-di-C₁₋₆alkyl amide such asN-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl orN,N-diethyl amide.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess cholesterolabsorption inhibitory activity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess cholesterol absorption inhibitoryactivity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess cholesterol absorption inhibitoryactivity.

Preferred aspects of the invention are those which relate to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof which process(wherein variable groups are, unless otherwise specified, as defined informula (I)) comprises of:

Process 1) Reacting a Compound of Formula (II):

with a compound of formula (III):

wherein L is a displaceable group;

Process 2) Reacting an Acid of Formula (IV):

or an activated derivative thereof; with an amine of formula (V):

Process 3): Reacting an Acid of Formula (VI):

or an activated derivative thereof, with an amine of formula (VII):

Process 4): Reducing a Compound of Formula (VIII):

Process 5): Reacting a Compound of Formula (IX):

with a compound of formula (X):

wherein L is a displaceable group;

Process 6): Reacting a Compound of Formula (XI):

wherein L is a displaceable group; with a compound of formula (XII):

Process 7): De-Esterifying a Compound of Formula (XIII)

wherein the group C(O)OR is an ester group;and thereafter if necessary or desirable:i) converting a compound of the formula (I) into another compound of theformula (I);ii) removing any protecting groups;iii) forming a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug; oriv) separating two or more enantiomers.

L is a displaceable group, suitable values for L are for example, ahalogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

C(O)OR is an ester group, suitable values for C(O)OR aremethoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and benzyloxycarbonyl.

The starting materials used in the present invention can be prepared bymodifications of the routes described in EP 0 792 264 B1. Alternativelythey can be prepared by the following reactions.

Process 1): Alcohols of formula (II) may be reacted with compounds offormula (III) in the presence of a base for example an inorganic basesuch as sodium carbonate, or an organic base such as Hunigs base, in thepresence of a suitable solvent such as acetonitrile, dichloromethane ortetrahydrofuran at a temperature in the range of 0° C. to reflux,preferably at or near reflux.

Compounds of formula (II) may be prepared according to the followingscheme:

wherein pMeOBz is para methoxy benzyl.

Compounds of formula (IIb), (IId), (IIg) and (III) are commerciallyavailable compounds, or they are known in the literature, or they areprepared by standard processes known in the art.

A compound of formula (III) may also be reacted with a compound offormula (XIV).

Compounds of formula (XIV) may be prepared according to the followingroute:

Compounds of formula XIVi may be prepared by the following route:

Process 2) and Process 3): Acids and amines may be coupled together inthe presence of a suitable coupling reagent. Standard peptide couplingreagents known in the art can be employed as suitable coupling reagents,for example carbonyldiimidazole and dicyclohexyl-carbodiimide,optionally in the presence of a catalyst such as dimethylaminopyridineor 4-pyrrolidinopyridine, optionally in the presence of a base forexample triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents includedimethylacetamide, dichloromethane, benzene, tetrahydrofuran anddimethylformamide. The coupling reaction may conveniently be performedat a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for exampleacid chlorides, and active esters, for example pentafluorophenyl esters.The reaction of these types of compounds with amines is well known inthe art, for example they may be reacted in the presence of a base, suchas those described above, and in a suitable solvent, such as thosedescribed above. The reaction may conveniently be performed at atemperature in the range of −40 to 40° C.

Acids of formula (IV) and (VI) may be prepared from compounds of formula(II) by reacting them with the appropriate, optionally protected, sidechain using the conditions of Process 1). Alternatively, acids offormula (IV) and (VI) may be prepared by a modification of Scheme I.

Amines of formula (V) and (VII) are commercially available compounds, orthey are known in the literature, or they are prepared by standardprocesses known in the art.

Process 4): Reduction of compounds of formula (VIII) could be performedwith a hydride reagent such as sodium borohydride in a solvent such asmethanol at temperatures suitable between −20-40° C.

Compounds of formula (VIII) can be prepared from compounds of formula(III), by deprotecting the benzyl group and performing Process 1.Alternatively compound (IIk) could be debenzylated, Process 1 could beperformed and the resulting compound deprotected to reveal the ketone.

Process 5) and Process 6): these compounds may be reacted together inthe presence of a base for example an inorganic base such as sodiumcarbonate, or an organic base such as Hunigs base, in the presence of asuitable solvent such as acetonitrile, dichloromethane ortetrahydrofuran at a temperature in the range of 0° C. to reflux,preferably at or near reflux.

Compounds of formula (IX) and (XI) may be prepared by an appropriatemodification of Scheme 1.

Compounds of formula (X) and (XII) are commercially available compounds,or they are known in the literature, or they are prepared by standardprocesses known in the art.

Process 7): Esters of formula (XIII) may be deprotected under standardconditions such as those described below, for example a methyl or ethylester may be deprotected with sodium hydroxide in methanol at roomtemperature.

Compounds of formula (XIII) may be prepared by a modification of any ofthe processes described herein for the preparation of compounds offormula (I).

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1999). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossess cholesterol absorption inhibitory activity. These properties maybe assessed, using the following biological tests.

In Vivo Testing of Cholesterol Absorption Inhibitors (A)

C57BL/6 female mice were maintained on regular chow diet and housed inindividual cages to collect faeces. Mice were fasted for 3 hours andthen gavaged with vehicle or compound. Half an hour later the mice weregavaged with radiolabelled cholesterol. Six hours after the¹⁴C-cholesterol gavage blood samples were taken via the tail and plasmaprepared to determine how much cholesterol were absorbed. 24 hours afterthe gavage of ¹⁴C-cholesterol the mice were bled and plasma wereprepared for analysis. Faeces were collected for 24 hours to assessabsorption efficiency.

In Vivo Testing of Cholesterol Absorption Inhibitors (B).

C57BL/6 female mice were maintained on regular chow diet and housed inindividual cages to collect faeces. Mice were fasted for 3 hours andthen gavaged with vehicle or compound. One to ten hours later the micewere gavaged with radiolabelled cholesterol. Six hours after the¹⁴C-cholesterol gavage blood sample was taken via the tail and plasmaprepared to determine how much cholesterol was absorbed. 24 hours afterthe gavage of ¹⁴C-cholesterol the mice were bled and plasma analysed forradioactivity. Faeces were also collected for 24 hours to assessabsorption efficiency.

REFERENCES

-   1. E. A. Kirk, G. L. Moe, M. T. Caldwell, J. Å. Lernmark, D. L.    Wilson, R. C. LeBoeuf. Hyper- and hypo-responsiveness to dietary fat    and cholesterol among inbred mice: searching for level and    variability genes. J. Lipid Res. 1995 36:1522-1532.-   2. C. P. Carter, P. N. Howles, D. Y. Hui. Genetic variation in    cholesterol absorption efficiency among inbred strains of mice. J.    Nutr. 1997 127:1344-1348.-   3. C. D. Jolley, J. M. Dietschy, S. D. Turley. Genetic differences    in cholesterol absorption in 129/Sv and C57BL/6 mice: effect on    cholesterol responsiveness. Am. J. Physiol. 1999 276:G1117-G1124.

Administration of 0.2 μmol/kg of Example 3 gave 73% inhibition of¹⁴C-cholesterol absorption (procedure A). Administration of 0.2 μmol/kgof Example 4 gave 75% inhibition of ¹⁴C-cholesterol absorption(procedure A) and administration of 0.2 μmol/kg of Example 5 gave 78%inhibition of ¹⁴C-cholesterol absorption (procedure A).

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, will normally beadministered to a warm-blooded animal at a unit dose within the range ofapproximately 0.02-100 mg/kg, preferably 0.02-50 mg/kg, and thisnormally provides a therapeutically-effective dose. A unit dose formsuch as a tablet or capsule will usually contain, for example 1-250 mgof active ingredient. Preferably a daily dose in the range of 1-50mg/kg, particularly 0.1-10 mg/kg is employed. In another aspect a dailydose in the rage of 0.01-20 mg/kg is employed. In one aspect of theinvention the daily dose of a compound of formula (I) is less than orequal to 100 mg. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use in a method of prophylactic or therapeutictreatment of a warm-blooded animal, such as man.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, are effective cholesterol absorption inhibitors, andaccordingly have value in the treatment of disease states associatedwith hyperlipidaemic conditions.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in theproduction of a cholesterol absorption inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the production of a cholesterol absorption inhibitoryeffect in a warm-blooded animal, such as man.

Herein, where the production of a cholesterol absorption inhibitoryeffect or a cholesterol lowering effect is stated, suitably this relatesto the treatment of hyperlipidaemic conditions in a warm-blooded animal,such as man. Additionally is relates to the treatment of dyslipidemicconditions and disorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL) in awarm-blooded animal, such as man. Furthermore it relates to thetreatment of different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocytes, monocytes and/or macrophage infiltration, intimalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaemic attacks in a warm-bloodedanimal, such as man. It also relates to the treatment ofatherosclerosis, coronary heart diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, stroke and transient ischaemicattacks in a warm-blooded animal, such as man.

The production of a cholesterol absorption inhibitory effect or acholesterol lowering effect also relates to a method of treating and/orpreventing atherosclerotic lesions, a method of preventing plaquerupture and a method of promoting lesion regression. Furthermore itrelates to a method of inhibiting monocytes-macrophage accumulation inatherosclerotic lesions, a method of inhibiting expression of matrixmetalloproteinases in atherosclerotic lesions, a method of inhibitingthe destabilization of atherosclerotic lesions, a method for preventingatherosclerotic plaque rupture and a method of treating unstable angina.

The production of a cholesterol absorption inhibitory effect or acholesterol lowering effect also relates to a method of treatingsitosterolemia.

Compounds of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof may also have valuein the treatment or prevention of Alzeheimer's Disease (see for exampleWO 02/096415). Therefore in a further aspect of the invention, there isprovided a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, for use inthe treatment or prevention of Alzeheimer's Disease.

Compounds of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof may also have valuein the treatment or prevention of vascular inflammation (see for exampleWO 03/026644). Therefore in a further aspect of the invention, there isprovided a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, for use inthe treatment or prevention of vascular inflammation.

According to a further feature of this aspect of the invention there isprovided a method for producing a cholesterol absorption inhibitoryeffect in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

The cholesterol absorption inhibitory activity defined hereinbefore maybe applied as a sole therapy or may involve, in addition to a compoundof the invention, one or more other substances and/or treatments. Suchconjoint treatment may be achieved by way of the simultaneous,sequential or separate administration of the individual components ofthe treatment. According to this aspect of the invention there isprovided a pharmaceutical product comprising a compound of the formula(I), or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof, as defined hereinbefore and an additionalcholesterol absorption inhibitory substance as defined hereinbefore andan additional hypolipidaemic agent for the conjoint treatment ofhyperlipidaemia.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with cholesterolbiosynthesis inhibitors, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable cholesterolbiosynthesis inhibitors include HMG Co-A reductase inhibitors, squalenesynthesis inhibitors and squalene epoxidase inhibitors. A suitablesqualene synthesis inhibitor is squalestatin 1 and a suitable squaleneepoxidase inhibitor is NB-598.

In this aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an HMG Co-Areductase inhibitor, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductaseinhibitors, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are statins well known in the art.Particular statins are fluvastatin, lovastatin, pravastatin,simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin,mevastatin and rosuvastatin, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof. A furtherparticular statin is pitvastatin, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof. A particularstatin is atorvastatin, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof. A more particular statin isatorvastatin calcium salt. A further particular statin is rosuvastatin,or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof. A preferable particular statin is rosuvastatincalcium salt.

Therefore in an additional feature of the invention, there is provided acombination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of an HMG Co-A reductaseinhibitor, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in a first unitdosage form;b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof; in a secondunit dosage form; andc) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, together with apharmaceutically acceptable diluent or carrier, in a first unit dosageform;b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a secondunit dosage form; andc) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the production of a cholesterol lowering effect.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofa matrix metalloproteinase inhibitor.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an ileal bileacid (IBAT) inhibitor or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof. Suitable compoundspossessing IBAT inhibitory activity for use in combination withcompounds of the present invention have been described, see for instancethe compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO94/24087, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO98/07749, WO 98/38182, WO 98/40375, WO 98/56757, WO 99/32478, WO99/35135, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/20392, WO00/20393, WO 00/20410, WO 00/20437, WO 00/35889, WO 01/34570, WO00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO00/47568, WO 00/61568, WO 01/66533, WO 01/68096, WO 01/68637, WO02/08211, DE 19825804, JP 10072371, U.S. Pat. No. 5,070,103, EP 251 315,EP 417 725, EP 489 423, EP 549 967, EP 573 848, EP 624 593, EP 624 594,EP 624 595, EP 864 582, EP 869 121 and EP 1 070 703 and the contents ofthese patent applications are incorporated herein by reference.Particularly the named examples of these patent applications areincorporated herein by reference. More particularly claim 1 of thesepatent application are incorporated herein by reference.

Other suitable classes of IBAT inhibitors for use in combination withcompounds of the present invention are the 1,2-benzothiazepines,1,4-benzothiazepines and 1,5-benzothiazepines. A further suitable classof IBAT inhibitors is the 1,2,5-benzothiadiazepines.

One particular suitable compound possessing IBAT inhibitory activity foruse in combination with compounds of the present invention is(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl□-D-glucopyranosiduronic acid (EP 864 582).

A further suitable compound possessing IBAT inhibitory activity for usein combination with compounds of the present invention is S-8921 (EP 597107).

A further suitable IBAT inhibitor for use in combination with compoundsof the present invention is the compound:

A particular IBAT inhibitor for use in combination with compounds of thepresent invention is selected from any one of Examples 1-120 of WO02/50051, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-120are incorporated herein by reference. Claims 1-15 of WO 02/50051 arealso incorporated herein by reference. A particular IBAT inhibitorselected from WO 02/50051 for use in combination with compounds of thepresent invention is selected from any one of:

-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)    carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(5-carboxypentyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phen    yl-7-methylthio-8-(N-{(R)-α-[N′—(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoyl-methoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{(R)-1-[N″-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(ethyl)    phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(hydroxy)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)—N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;    and-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

A particular IBAT inhibitor for use in combination with compounds of thepresent invention is selected from any one of Examples 1-44 of WO03/020710, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-44 areincorporated herein by reference. Claims 1-10 of WO 03/020710 are alsoincorporated herein by reference. A particular IBAT inhibitor selectedfrom WO 03/020710 for use in combination with compounds of the presentinvention is selected from any one of:

-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carbamoyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(hydroxycarbamoyl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N—((R)-α-{N′-[2-(N′-pyrimidin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N—((R)-α-{N′-[2-(N′-pyridin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(1-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2,3-dihydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N—((R)-α-{N′-[2-(3,4-dihydroxyphenyl)-2-methoxyethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-aminoethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(piperidin-4-ylmethyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;    or-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-N,N-dimethylaminosulphamoylethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

A particular IBAT inhibitor for use in combination with compounds of thepresent invention is selected from any one of Examples 1-7 of WO03/022825, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-7 areincorporated herein by reference. Claims 1-8 of WO 03/022825 are alsoincorporated herein by reference. A particular IBAT inhibitor selectedfrom WO 03/022825 for use in combination with compounds of the presentinvention is selected from any one of:

-   1,1-dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-[N—((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   1,1-dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-[(N—((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   1,1-dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   1,1-dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   3,5-trans-1,1-dioxo-3-(S)-3-ethyl-3-butyl-4-hydroxy-5-(S)-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine-   3,5-trans-1,1-dioxo-3-(R)-3-ethyl-3-butyl-4-hydroxy-5-(R)-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine    ammonia salt;-   1,1-dioxo-3-(S)-3-ethyl-3-butyl-5-(S)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine    diethylamine salt; and-   1,1-dioxo-3-(R)-3-ethyl-3-butyl-5-(R)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine    diethylamine salt;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

A particular IBAT inhibitor for use in combination with compounds of thepresent invention is selected from any one of Examples 1-4 of WO03/022830, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 14 areincorporated herein by reference. Claims 1-8 of WO 03/022830 are alsoincorporated herein by reference. A particular IBAT inhibitor selectedfrom WO 03/022830 for use in combination with compounds of the presentinvention is selected from any one of:

-   1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine-   1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine    ammonia salt-   1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{N-[α-(carboxy)-2-fluorobenzyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepine;    and-   1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{N-[1-(carboxy)-1-(thien-2-yl)methyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepine    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

A particular IBAT inhibitor for use in combination with compounds of thepresent invention is selected from any one of Examples 1-39 of WO03/022286, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-39 areincorporated herein by reference. Claims 1-10 of WO 03/022286 are alsoincorporated herein by reference. A particular IBAT inhibitor selectedfrom WO 03/022286 for use in combination with compounds of the presentinvention is selected from any one of:

-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxybutyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxypropyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N—((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxypropyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    and-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

A particular MAT inhibitor for use in combination with compounds of thepresent invention is selected from any one of Examples 1-7 of WO03/091232, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-7 areincorporated herein by reference. Claims 1-10 of WO 03/091232 are alsoincorporated herein by reference. A particular MAT inhibitor selectedfrom WO 03/091232 for use in combination with compounds of the presentinvention is selected from any one of:

-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N-{2-(S)—[N-(carbamoylmethyl)    carbamoyl]pyrrolidin-1-ylcarbonylmethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-α-{N-[2-(3,4,5-trihydroxyphenyl)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    and-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(R)-3-(S)-4-(S)-5-(R)-3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

Further suitable compounds possessing IBAT inhibitory activity for usein combination with compounds of the present invention have thefollowing structure of formula (AI):

wherein:

R¹ and R² are independently selected from C₁₋₄alkyl;

R³ is hydrogen, hydroxy or halo;

R⁴ is C₁₋₄alkyl optionally substituted by hydroxy, methoxy andmethylS(O)a wherein a is 0-2

R⁵ is hydroxy or HOC(O)CH(R⁶)NH—;

R⁶ is selected from hydrogen and C₁₋₃alkyl optionally substituted byhydroxy, methoxy and methylS(O)a wherein a is 0-2;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof;with the proviso that when R¹ and R² are both butyl, R⁵ is hydroxy andR⁴ is methylthiomethyl, methylsulphinylmethyl, methylthiomethyl,hydroxymethyl, methoxymethyl; R³ is not hydrogen; and with the provisothat when R¹ and R² are both butyl, R⁵ is HOC(O)CH(R⁶)NH—, R⁶ ishydroxymethyl and R⁴ is hydroxymethyl; R³ is not hydrogen.

Suitable IBAT inhibitors having the above structure for use incombination with compounds of the present invention are selected fromany one of:

-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxybutyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-3-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-mesylethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-3-methylsulphonylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-3-mesylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxyethyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxypropyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxybutyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methyl    thio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-methylbutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-3-methylbutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-hydroxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-methylthioethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((8)-1-carboxy-2-methylsulphinylethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-mesylethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-2-methoxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-3-methylthiopropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-3-methylsulphonylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxy-3-mesylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;    or-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′—((S)-1-carboxyethyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine.    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

Further suitable IBAT inhibitors for use in combination with compoundsof the present invention are those having the structure (BI):

wherein

M¹ is —CH₂— or —NR²¹—;

M² is —CR²²R²³— or —NR²⁴—; provided that if M¹ is —NR²¹—, M² is—CR²²R²³—;

One of R¹ and R² are selected from hydrogen, C₁₋₆alkyl or C₂₋₆alkenyland the other is selected from C₁₋₆alkyl or C₂₋₆alkenyl;

R³ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

v is 0-5;

one of R⁵ and R⁶ is a group of formula (BIA):

R⁴ and R⁷ and the other of R⁵ and R⁶ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R⁴ and R⁷ and the other of R⁵ and R⁶may be optionally substituted on carbon by one or more R²⁵;

Z is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

R⁸ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁸ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁶; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁷;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ and R¹¹ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; or R¹⁰ and R¹¹ together form C₂₋₆alkylene;wherein R¹⁰ and R¹¹ or R¹⁰ and R¹¹ together may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁸; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R²⁹;

R¹² is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹² maybe optionally substituted on carbon by one or more substituents selectedfrom R³⁰; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R³¹;

R¹³ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀-alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀-alkoxy, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀-alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀-alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀-alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀-alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀-alkyl,heterocyclic group, heterocyclylC₁₋₁₀-alkyl,carbocyclyl-(C₁₋₁₀-alkylene)_(e)-R³²—(C₁₋₁₀-alkylene)_(f)- orheterocyclyl-(C₁₋₁₀alkylene)_(g)-R³³—(C₁₋₁₀ alkylene)_(h)-; wherein R¹³may be optionally substituted on carbon by one or more substituentsselected from R³⁶; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁷; or R¹³ is a group of formula (BIB):

wherein:

X is —N(R³⁸)—, —N(R³⁸)C(O)—, —O—, and —S(O)_(a)—; wherein a is 0-2 andR³⁸ is hydrogen or C₁₋₄alkyl;

R¹⁴ is hydrogen or C₁₋₄alkyl;

R¹⁵ and R¹⁶ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆ alkyl)₂amino, C₁₋₆ alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, carbocyclyl or heterocyclic group; whereinR¹⁵ and R¹⁶ may be independently optionally substituted on carbon by oneor more substituents selected from R⁴¹; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R⁴²;

R¹⁷ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀-alkoxy, C₁₋₁₀-alkanoyl,C₁₋₁₀-alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀ alkyl)₂amino,C₁₋₁₀-alkanoylamino, N—(C₁₋₁₀-alkyl)carbamoyl, C₁₋₁₀-alkoxycarbonyl,N,N—(C₁₋₁₀alkyl)₂-carbamoyl, C₁₋₁₀-alkyl S(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀-alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀-alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,carbocyclyl, carbocyclylC₁₋₁₀-alkyl, heterocyclic group,heterocyclylC₁₋₁₀-alkyl,carbocyclyl-(C₁₋₁₀-alkylene)_(e)-R⁴³—(C₁₋₁₀-alkylene)_(f)- orheterocyclyl-(C₁₋₁₀ alkylene)_(g)-R⁴⁴—(C₁₋₁₀alkylene)_(h)-; wherein R¹⁷may be optionally substituted on carbon by one or more substituentsselected from R⁴⁷; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R⁴⁸; or R¹⁷ is a group of formula (BIC):

wherein:

R¹⁸ is selected from hydrogen or C₁₋₄alkyl;

R¹⁹ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂-carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,carbocyclyl or heterocyclic group; where R¹⁹ may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R⁵¹; and wherein if said heterocyclyl contains an —NH-group, thatnitrogen may be optionally substituted by a group selected from R⁵²;

R²⁰ is selected from halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀-alkyl, C₂₋₄₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀-alkoxy, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkanoyl,C₁₋₁₀-alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀-alkyl)₃ammonio, C₁₋₁₀-alkanoylamino,N—(C₁₋₁₀-alkyl)carbamoyl, N,N—(C₁₋₁₀-alkyl)₂carbamoyl,C₁₋₁₀-alkylS(O)_(a), wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀-alkyl)sulphamoylamino,N,N—(C₁₋₁₀-alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino,carbocyclyl, carbocyclylC₁₋₁₀-alkyl, heterocyclic group,heterocyclylC₁₋₁₀-alkyl,carbocyclyl-(C₁₋₁₀-alkylene)_(e)-R⁵³—(C₁₋₁₀alkylene)_(f)- orheterocyclyl-(C₁₋₁₀-alkylene)_(g)-R⁵⁴—(C₁₋₁₀alkylene)_(h)-; wherein R²⁰may be independently optionally substituted on carbon by one or moreR⁵⁷; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R⁵⁸;

p is 1-3; wherein the values of R¹⁵ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁶ may be the same or different;

m is 0-2; wherein the values of R¹² may be the same or different;

n is 1-2; wherein the values of R⁸ may be the same or different;

z is 0-3; wherein the values of R¹⁹ may be the same or different;

R²¹ is selected from hydrogen or C₁₋₆alkyl;

R²² and R²³ are independently selected from hydrogen, hydroxy, amino,mercapto, C₁₋₆alkyl, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

R²⁴ is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₄alkoxy andC₁₋₆alkanoyloxy;

R²⁵ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R²⁵, may be independently optionallysubstituted on carbon by one or more R⁶⁷;

R²⁶, R²⁸, R³⁰, R³⁶, R⁴¹, R⁴⁷, R⁵¹ and R⁵⁷ are independently selectedfrom halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkenyl, C₂₋₁₀alkyenyl,C₁₋₁₀-alkoxy, C₁₋₁₀-alkanoyl, C₁₋₁₀alkanoyloxy, C₁₋₁₀alkoxycarbonyl,N—(C₁₋₁₀-alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀-alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀-alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀-alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀-alkyl,heterocyclic group, heterocyclylC₁₋₁₀ alkyl,carbocyclyl-(C₁₋₁₀-alkylene)_(e)-R⁵⁹—(C₁₋₁₀-alkylene)_(f)- orheterocyclyl-(C₁₋₁₀-alkylene)_(g)-R⁶⁰—(C₁₋₁₀alkylene)_(h); wherein R²⁶,R²⁸, R³⁰, R³⁶, R⁴¹, R⁴⁷, R⁵¹ and R⁵⁷ may be independently optionallysubstituted on carbon by one or more R⁶³; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R⁶⁴;

R²⁷, R²⁹, R³¹, R³⁷, R⁴², R⁴⁸, R⁵², R⁵⁸ and R⁶⁴ are independentlyselected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₄alkylsulphonyl, sulphamoyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂-carbamoyl, benzyl,phenethyl, benzoyl, phenylsulphonyl and phenyl; R³², R³³, R⁴³, R⁴⁴, R⁵³,R⁵⁴, R⁵⁹ and R⁶⁰ are independently selected from —O—, —NR⁶⁵—,—S(O)_(x)—, —NR⁶⁵C(O)NR⁶⁶—, —NR⁶⁵C(S)NR⁶⁶—, —OC(O)N═C—, —NR⁶⁵C(O)— or—C(O)NR⁶⁵—; wherein R⁶⁵ and R⁶⁶ are independently selected from hydrogenor C₁₋₆alkyl, and x is 0-2;

R⁶³ and R⁶⁷ are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido,acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,N-methylsulphamoyl and N,N-dimethylsulphamoyl; and

e, f, g and h are independently selected from 0-2;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Additional suitable IBAT inhibitors having the above structure for usein combination with compounds of the present invention are selected fromany one of:

-   (+/−)-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   (+/−)-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;-   1,1-dioxo-3-ethyl-3-butyl-4-hydroxy-5-phenyl-7-(N-{α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-2-fluorobenzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiapine;    or-   1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{1-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-1-(cyclohexyl)methyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine.

Compounds of formula (AI) and (BI) or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof may beprepared by processes known in the art.

In a particular aspect of the invention an IBAT inhibitor or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof is an IBAT inhibitor or a pharmaceutically acceptablesalt thereof.

Therefore in an additional feature of the invention, there is provided acombination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of an IBAT inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an IBAT inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, inassociation with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in a first unitdosage form;b) an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof; in a second unit dosageform; andc) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, together with apharmaceutically acceptable diluent or carrier, in a first unit dosageform;b) an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in a second unit dosageform; andc) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an IBATinhibitor, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, in the manufacture of a medicament foruse in the production of a cholesterol lowering effect in a warm-bloodedanimal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an MAT inhibitor, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a PPAR alphaand/or gamma agonist, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/orgamma agonists, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are well known in the art. These includethe compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO99/62872, WO 99/62871, WO 98/57941, WO 01/40170, WO03/051821,WO03/051822, WO03/051826, PCT/GB03/02584, PCT/GB03/02591,PCT/GB03/02598, J Med Chem, 1996, 39, 665, Expert Opinion on TherapeuticPatents, 10 (5), 623-634 (in particular the compounds described in thepatent applications listed on page 634) and J Med Chem, 2000, 43, 527which are all incorporated herein by reference.

Particularly a PPAR alpha and/or gamma agonist refers to WY-14643,clofibrate, fenofibrate, bezafibrate, GW 9578, troglitazone,pioglitazone, rosiglitazone, eglitazone, proglitazone,NN622/Ragaglitazar, BMS 298585, BRL-49634, KRP-297, JTT-501, SB 213068,GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433. Particularlya PPAR alpha and/or gamma agonist refers to(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoicacid and pharmaceutically acceptable salts thereof.

Therefore in an additional feature of the invention, there is provided acombination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a PPAR alpha and/or gammaagonist, or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in a first unitdosage form;b) a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof; in a secondunit dosage form; andc) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, together with apharmaceutically acceptable diluent or carrier, in a first unit dosageform;b) a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a secondunit dosage form; andc) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a PPAR alphaand/or gamma agonist, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in producing a cholesterol lowering effect in awarm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a nicotinicacid derivative or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof. As used herein “nicotinic acidderivative” means a compounds comprising a pyridine-3-carboxylatestructure or a pyrazine-2-carboxylate structure. Examples of nicotinicacid derivatives include nicotinic acid, niceritrol, nicofuranose,NIASPAN® and acipimox.

Therefore, in an additional feature of the invention, there is provideda combination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a nicotinic acid derivative or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a nicotinic acid derivative,or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a nicotinic acid derivative, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in association with a pharmaceutically acceptable diluent or carrier.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a nicotinicacid derivative, or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof, in the manufacture of a medicamentfor use in the production of a cholesterol lowering effect in awarm-blooded animal, such as man.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a bile acidsequestrant or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof. Suitable bile acid sequestrantsinclude cholestyramine, cholestipol and cosevelam hydrochloride.

Therefore, in an additional feature of the invention, there is provideda combination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a bile acid sequestrant or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a bile acid sequestrant, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid sequestrant, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in association with a pharmaceutically acceptable diluent or carrier.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a bile acidsequestrant, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, in the manufacture of a medicament foruse in the production of a cholesterol lowering effect in a warm-bloodedanimal, such as man.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from Group X:

-   -   an antihypertensive compound (for example althiazide,        benzthiazide, captopril, carvedilol, chlorothiazide sodium,        clonidine hydrochloride, cyclothiazide, delapril hydrochloride,        dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,        guanfacine hydrochloride, methyldopa, metoprolol succinate,        moexipril hydrochloride, monatepil maleate, pelanserin        hydrochloride, phenoxybenzemine hydrochloride, prazosin        hydrochloride, primidolol, quinapril hydrochloride, quinaprilat,        ramipril, terazosin hydrochloride, candesartan, candesartan        cilexetil, telmisartan, amlodipine besylate, amlodipine maleate        and bevantolol hydrochloride);    -   an angiotensin converting enzyme inhibitor (for example        alacepril, alatriopril, altiopril calcium, ancovenin,        benazepril, benazepril hydrochloride, benazeprilat,        benzoylcaptopril, captopril, captopril-cysteine,        captopril-glutathione, ceranapril, ceranopril, ceronapril,        cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril,        enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril,        fosenopril, fosenopril sodium, fosinopril, fosinopril sodium,        fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,        idrapril, imidapril, indolapril, indolaprilat, libenzapril,        lisinopril, lyciumin A, lyciumin B, mixanpril, moexipril,        moexiprilat, moveltipril, muracein A, muracein B, muracein C,        pentopril, perindopril, perindoprilat, pivalopril, pivopril,        quinapril, quinapril hydrochloride, quinaprilat, ramipril,        ramiprilat, spirapril, spirapril hydrochloride, spiraprilat,        spiropril, spiropril hydrochloride, temocapril, temocapril        hydrochloride, teprotide, trandolapril, trandolaprilat,        utibapril, zabicipril, zabiciprilat, zofenopril and        zofenoprilat);    -   an angiotensin II receptor antagonist (for example candesartan,        candesartan cilexetil, losartan, valsartan, irbesartan,        tasosartan, telmisartan and eprosartan);    -   an andrenergic blocker (for example bretylium tosylate,        dihydroergotamine so mesylate, phentolamine mesylate,        solypertine tartrate, zolertine hydrochloride, carvedilol or        labetalol hydrochloride); an alpha andrenergic blocker (for        example fenspiride hydrochloride, labetalol hydrochloride,        proroxan and alfuzosin hydrochloride); a beta andrenergic        blocker (for example acebutolol, acebutolol hydrochloride,        alprenolol hydrochloride, atenolol, bunolol hydrochloride,        carteolol hydrochloride, celiprolol hydrochloride, cetamolol        hydrochloride, cicloprolol hydrochloride, dexpropranolol        hydrochloride, diacetolol hydrochloride, dilevalol        hydrochloride, esmolol hydrochloride, exaprolol hydrochloride,        flestolol sulfate, labetalol hydrochloride, levobetaxolol        hydrochloride, levobunolol hydrochloride, metalol hydrochloride,        metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate,        penbutolol sulfate, practolol, propranolol hydrochloride,        sotalol hydrochloride, timolol, timolol maleate, tiprenolol        hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate and        nebivolol); or a mixed alpha/beta andrenergic blocker;    -   an andrenergic stimulant (for example combination product of        chlorothiazide and methyldopa, the combination product of        methyldopa hydrochlorothiazide and methyldopa, clonidine        hydrochloride, clonidine, the combination product of        chlorthalidone and clonidine hydrochloride and guanfacine        hydrochloride);    -   channel blocker, for example a calcium channel blocker (for        example clentiazem maleate, amlodipine besylate, isradipine,        nimodipine, felodipine, nilvadipine, nifedipine, teludipine        hydrochloride, diltiazem hydrochloride, belfosdil, verapamil        hydrochloride or fostedil);    -   a diuretic (for example the combination product of        hydrochlorothiazide and spironolactone and the combination        product of hydrochlorothiazide and triamterene);    -   anti-anginal agents (for example amlodipine besylate, amlodipine        maleate, betaxolol hydrochloride, bevantolol hydrochloride,        butoprozine hydrochloride, carvedilol, cinepazet maleate,        metoprolol succinate, molsidomine, monatepil maleate,        primidolol, ranolazine hydrochloride, tosifen or verapamil        hydrochloride);    -   vasodilators for example coronary vasodilators (for example        fostedil, azaclorzine hydrochloride, chromonar hydrochloride,        clonitrate, diltiazem hydrochloride, dipyridamole,        droprenilamine, erythrityl tetranitrate, isosorbide dinitrate,        isosorbide mononitrate, lidoflazine, mioflazine hydrochloride,        mixidine, molsidomine, nicorandil, nifedipine, nisoldipine,        nitroglycerine, oxprenolol hydrochloride, pentrinitrol,        perhexyline maleate, prenylamine, propatyl nitrate, terodiline        hydrochloride, tolamolol and verapamil);    -   anti-coagulants (selected from argatroban, bivalirudin,        dalteparin sodium, desirudin, dicumarol, Iyapolate sodium,        nafamostat mesylate, phenprocoumon, tinzaparin sodium and        warfarin sodium);    -   antithrombotic agents (for example anagrelide hydrochloride,        bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium,        dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium,        fluretofen, ifetroban, ifetroban sodium, lamifiban, lotrafiban        hydrochloride, napsagatran, orbofiban acetate, roxifiban        acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab        and zolimomab aritox);    -   fibrinogen receptor antagonists (for example roxifiban acetate,        fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban,        xemilofiban, monoclonal antibody 7E3 and sibrafiban)    -   platelet inhibitors (for example cilostezol, clopidogrel        bisulfate, epoprostenol, epoprostenol sodium, ticlopidine        hydrochloride, aspirin, ibuprofen, naproxen, sulindae,        indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone        and piroxicam, dipyridamole);    -   platelet aggregation inhibitors (for example acadesine,        beraprost, beraprost sodium, ciprostene calcium, itezigrel,        lifarizine, lotrafiban hydrochloride, orbofiban acetate,        oxagrelate, fradafiban, orbofiban, tirofiban and xemilofiban)    -   hemorrheologic agents (for example pentoxifylline);    -   lipoprotein associated coagulation inhibitors;    -   Factor VIIa inhibitors;    -   Factor Xa inhibitors;    -   low molecular weight heparins (for example enoxaparin,        nardroparin, dalteparin, certroparin, parnaparin, reviparin and        tinzaparin);    -   squalene synthase inhibitors;    -   squalene epoxidase inhibitors;    -   liver X receptor (LXR) agonists for example GW-3965 and those        described in WO00224632, WO00103705, WO02090375 and WO00054759        (claim 1 and the named examples of these four application are        incorporated herein by reference);    -   microsomal triglyceride transfer protein inhibitors for example        implitapide and those described in WO03004020, WO03002533,        WO02083658 and WO 00242291 (claim 1 and the named examples of        these four application are incorporated herein by reference);        or a pharmaceutically acceptable salt, solvate, solvate of such        a salt or a prodrug thereof, optionally together with a        pharmaceutically acceptable diluent or carrier to a warm-blooded        animal, such as man in need of such therapeutic treatment.

Therefore, in an additional feature of the invention, there is provideda combination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a compound from Group X or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a compound from Group X, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a compound from Group X, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in association with a pharmaceutically acceptable diluent or carrier.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a compoundfrom Group X, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, in the manufacture of a medicament foruse in the production of a cholesterol lowering effect in a warm-bloodedanimal, such as man.

In addition to their use in therapeutic medicine, the compounds offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, are also useful as pharmacologicaltools in the development and standardisation of in vitro and in vivotest systems for the evaluation of the effects of inhibitors ofcholesterol absorption in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

Many of the intermediates described herein are novel and are thusprovided as a further feature of the invention. For example compounds offormula (VI) show cholesterol absorption inhibitory activity when testedin the above referenced in vitro test assay and are thus claimed as afurther feature of the invention.

Thus in a further feature of the invention, there is provided a compoundof formula (VI), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof, with the proviso that said compoundis not3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

Therefore according to a further aspect of the invention there isprovided a pharmaceutical composition which comprises a compound offormula (VI), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in association with apharmaceutically-acceptable diluent or carrier, with the proviso thatsaid compound is not3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

According to an additional aspect of the present invention there isprovided a compound of the formula (VI), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,for use in a method of prophylactic or therapeutic treatment of awarm-blooded animal, such as man, with the proviso that said compound isnot3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

Thus according to this aspect of the invention there is provided acompound of the formula (VI), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, for use as amedicament, with the proviso that said compound is not3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

According to another feature of the invention there is provided the useof a compound of the formula (VI), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in themanufacture of a medicament for use in the production of a cholesterolabsorption inhibitory effect in a warm-blooded animal, such as man, withthe proviso that said compound is not3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

According to another feature of the invention there is provided the useof a compound of the formula (VI), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in themanufacture of a medicament for use in the treatment of hyperlipidaemicconditions in a warm-blooded animal, such as man, with the proviso thatsaid compound is not3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

According to a further feature of this aspect of the invention there isprovided a method for producing a cholesterol absorption inhibitoryeffect in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (VI), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, with the provisothat said compound is not3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (VI), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof, with the proviso that said compoundis not3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated in the following non limitingExamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these Examples may be usedwhere appropriate, and in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork up procedures were carried out after removal of residual solidssuch as drying agents by filtration;(ii) all reactions were carried out under an inert atmosphere at ambienttemperature, typically in the range 18-25° C., with solvents of HPLCgrade under anhydrous conditions, unless otherwise stated;(iii) column chromatography (by the flash procedure) was performed onSilica gel 40-63 μm (Merck);(iv) yields are given for illustration only and are not necessarily themaximum attainable;(v) the structures of the end products of the formula (I) were generallyconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; magnetic resonance chemical shift values weremeasured in deuterated CDCl₃ (unless otherwise stated) on the deltascale (ppm downfield from tetramethylsilane); proton data is quotedunless otherwise stated; spectra were recorded on a Varian Mercury-300MHz, Varian Unity plus-400 MHz, Varian Unity plus-600 MHz or on VarianInova-500 MHz spectrometer unless otherwise stated data was recorded at400 MHz; and peak multiplicities are shown as follows: s, singlet; d,doublet; dd, double doublet; t, triplet; tt, triple triplet; q, quartet;tq, triple quartet; m, multiplet; br, broad; ABq, AB quartet; ABd, ABdoublet, ABdd, AB doublet of doublets; dABq, doublet of AB quartets;LCMS were recorded on a Waters ZMD, LC, column xTerra MS C₈(Waters),detection with a HP 1100 MS-detector diode array equipped; mass spectra(MS) (loop) were recorded on VG Platform II (Fisons Instruments) with aHP-1100 MS-detector diode array equipped; unless otherwise stated themass ion quoted is (MH⁺); unless further details are specified in thetext, analytical high performance liquid chromatography (HPLC) wasperformed on Prep LC 2000 (Waters), Cromasil C₈, 7 μm, (Akzo Nobel);MeCN and de-ionised water 10 mM ammonium acetate as mobile phases, withsuitable composition;(vii) intermediates were not generally fully characterised and puritywas assessed by thin layer chromatography (TLC), HPLC, infra-red (IR),MS or NMR analysis;(viii) where solutions were dried sodium sulphate was the drying agent;and(ix) the following abbreviations may be used hereinbefore orhereinafter:—DCM dichloromethane;

DMF N,N-dimethylformamide;

TBTU o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate;EtOAc ethyl acetate;MeCN acetonitrile;TFA trifluoroacetic acid;DMAP 4-(dimethylamino)pyridine;

BSA N,O-Bis(trimethylsilyl)acetamide; and

TBAF tetrabutylammonium fluoride.

Example 1 N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valineN-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valine

The diastereomers ofN-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valinewere partly separated on a Kromasil C8-column using 35% MeCN in 0.1Mammonium acetate buffer as eluent.

First diastereomer eluated and analyzed on a Chiralpak AD column (10μ,4.6*250 mm, 1 mL/min, mobile phase:Heptane/Isopropanol/Formic acid65/35/0.1) at 254.00 nm to give a d.e=68%. Retention time at 26.44.

Example 2 1-[(N-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[(2R orS)-2-(4-chlorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]cyclopropanecarboxylicacid

To a 30° C. solution ofN-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine(0.030 g, 0.052 mmol and N-methylmorpholine (0.016 g, 0.157 mmol) inCH₂Cl₂ (5 ml) was added TBTU (0.020 g, 0.063 mmol). After 1 h,1-amino-1-cyclopropanecarboxylic acid (0.006 g, 0.063 mmol) was added.After 1 h, the reaction was quenched by the addition of water (1 ml).The reaction mixture was concentrated and to the residue was added MeOH(3 ml) and NaBH₄ (0.020 g, 0.523 mmol). Full conversion to thecorresponding alcohol was achieved after 5 minutes. The reaction wasquenched by the addition of 0.1M NH₄OAc buffer (1 ml) followed byconcentration. The residue was purified through preparative HPLC usingan eluent of 0-50% CH₃CN in 0.1M NH₄OAc buffer. This gave separation ofthe two diastereomers (epimers at the benzylic alcohol position). Freezedrying of each of the two fractions afforded the individual purediastereomers as colourless solids (combined yield 0.008 g, 23%). Firsteluting fraction: ¹H NMR [(CD₃)₂SO), 400 MHz] δ 0.90-0.93 (m, 2H),1.19-1.26 (m, 2H), 2.89-2.92 (m, 2H), 3.69-3.71 (m, 2H), 4.26-4.29 (m,1H), 4.51 (s, 2H), 4.69-4.74 (m, 1H), 5.05-5.07 (m, 1H), 6.98 (d, 2H),7.20 (d, 2H), 7.30-7.38 (m, 8H), 7.78-7.82 (m, 1H), 8.17-8.22 (m, 1H).second eluting fraction: ¹H NMR [(CD₃)₂SO), 400 MHz] δ 0.89-0.92 (m,2H), 1.20-1.25 (m, 2H), 2.88-2.90 (m, 2H), 3.68-3.71 (m, 2H), 4.28-4.31(m, 1H), 4.47-4.51 (m, 2H), 4.71-4.75 (m, 1H), 5.02-5.04 (m, 1H), 6.98(d, 2H), 7.17-7.36 (m, 10H), 7.79-7.83 (m, 1H), 8.18-8.21 (m, 1H).

Example 3 N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or6)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-methyl-D-valine

To a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine(0.19 g, 0.35 mmol) in DMF (5 ml) under an atmosphere of nitrogen wasadded N-methyl morpholine (0.12 g, 1.23 mmol) followed by the additionof TBTU (0.15 g, 0.46 mmol). After 1 h, 3-methyl-D-valine (0.064 g, 0.49mmol) was added. After 30 minutes, the reaction was quenched by theaddition of water (1 ml). After an additional 15 minutes, the reactionmixture was purified through preparative HPLC using an eluent of 10-50%CH₃CN in 0.1M NH₄OAc buffer. Freeze drying of pure fractions affordedthe desired compound (0.17 g, 74%) as a colourless solid. ¹HNMR[(CD₃)₂SO), 400 MHz] δ 0.90 (s, 9H), 2.91 (d, 2H), 3.84 (d, 2H), 4.11(d, 1H), 4.25 (d, 1H), 4.51 (s, 2H), 4.70 (t, 1H), 5.06 (d, 1H), 5.63(s, br, 1H), 6.97-7.37 (m, 12H), 7.91-7.94 (m, 1H), 8.23 (t, 1H).

Example 4 N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-cyclohexyl-D-alanine

To a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine(0.14 g, 0.26 mmol) in DMF (4 ml) under an atmosphere of nitrogen wasadded N-methyl morpholine (0.091 g, 0.90 mmol) followed by the additionof TBTU (0.108 g, 0.34 mmol). After 1 h, 3-cyclohexyl-D-alanine (0.062g, 0.36 mmol) was added. After 30 minutes, the reaction was quenched bythe addition of water (1 ml). After an additional 15 minutes, thereaction mixture was purified through preparative HPLC using an eluentof 10-50% CH₃CN in 0.1M NH₄OAc buffer.

Freeze drying of pure fractions afforded the desired compound (0.093 g,52%) as a colourless solid. ¹H NMR [(CD₃)₂SO), 400 MHz] δ 0.76-1.67 (m,13H), 2.89-2.93 (m, 2H), 3.76 (d, 2H), 4.15-4.21 (m, 1H), 4.26 (d, 1H),4.51 (s, 2H), 4.70 (t, 1H), 5.06 (d, 1H), 6.97-7.37 (m, 12H), 8.01 (d,1H), 8.22 (t, 1H).

Example 5 N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-β,β-dimethyl-D-phenylalanine

To a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine(0.020 g, 0.037 mmol) in DMF (2 ml) under an atmosphere of nitrogen wasadded N-methyl morpholine (0.015 g, 0.147 mmol) followed by the additionof TBTU (0.015 g, 0.048 mmol). After 1 h, β,β-dimethyl-D-phenylalaninetrifluoroacetate salt (0.016 g, 0.052 mmol) was added. After 30 minutes,the reaction was quenched by the addition of water (1 ml). After anadditional 15 minutes, the reaction mixture was purified throughpreparative HPLC using an eluent of 10-50% CH₃CN in 0.1M NH₄OAc buffer.Freeze drying of pure fractions afforded the desired compound (0.020 g,76%) as a colourless solid. ¹H NMR [(CD₃)₂SO), 400 MHz] δ 1.28 (s, 3H),1.30 (s, 3H), 2.88-2.93 (m, 2H), 3.62 (dd, 1H), 3.78 (dd, 1H), 4.28 (d,1H), 4.49 (s, 2H), 4.50 (d, 1H), 4.71 (t, 1H), 5.05 (d, 1H), 6.94-7.35(m, 17H), 7.66 (d, 1H), 8.22 (t, 1H).

Example 6 N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine

N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-N⁶-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-lysine(0.010 g, 0.011 mmole) was dissolved in 0.5 mL of piperidine in DMF (23%by volume). After 5 minutes the solvent was removed under reducedpressure and the residue was purified by preparative HPLC on a KromasilC8-column using a gradient of 5-100% MeCN in 0.1M ammonium acid bufferas eluent. After removing the solvent under reduced pressure andfreeze-drying from water, 0.0065 g (86%) of the desired product wasobtained.

NMR (500 MHz, CD₃COOD) 1.36-1.47 (m, 2H), 1.60-1.76 (m, 3H), 1.86-1.96(m, 1H), 2.87-2.94 (m, 2H), 2.97-3.09 (m, 2H), 3.97 (ABq, 2H), 4.05 (d,1H), 4.29 (dd, 1H), 4.64 (s, 2H), 4.81-4.87 (m, 1H), 4.93 (d, 1H),6.99-7.06 (m, 4H), 7.06-7.11 (m, 2H), 7.28-7.32 (m, 2H), 7.34-7.40 (m,4H)

PREPARATION OF STARTING MATERIALS FOR THE ABOVE EXAMPLES Methods Method1N-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine

To a stirred solution of[4-((2R,3R)-1-(4-chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]aceticacid, 302.1 mg, 0.585 mmol) in DCM (6 ml) were added N-methylmorpholine(190 μl, 1.728 mmol) and tert-butyl glycinate hydrochloride (133.4 mg,0.80 mmol). After 10 minutes TBTU (224.3 mg, 0.67 mmol) was added andthe reaction mixture was stirred at ambient temperature for 60 hours.The intermediate tert-butylester of the title compound was confirmed.M/z: 626.88 (M−H). DCM (10 ml) and water (15 ml) were added and themixture was acidified to pH of 3 with KHSO₄ (2M). The organic phase waswashed with water (2×15 ml), the combined water phases were extractedwith DCM (10 ml), dried over Na₂SO₄, filtered and the solvent wasevaporated off. A solution of the residue (500 mg) in DCM (10 ml) andTFA (4 ml) was stirred at ambient temperature overnight. The solvent wasremoved under reduced presssure, toluene was used to assist the removalof TFA. The residue was purified with preparative HPLC on a C8 column. Agradient from 20 to 50% MeCN in 0.1M ammonium acetate buffer was used aseluent. After lyophilisation, the title compound was obtained as a whitesolid (166.9 mg, 50%). ¹H-NMR (400 MHz, DMS-d₆): 3.51 (d, 2H), 4.33 (d,1H), 4.34 (s, 1H), 4.36 (s, 1H), 4.47 (s, 2H), 5.17 (d, 1H), 6.96 (d,2H), 7.16-7.21 (m, 2H), 7.35 (d, 4H), 7.54-7.59 (m, 2H), 7.83-7.90 (brs,1H), 7.91-7.95 (m, 2H). M/z: 571.04 (M−H) and 572.88 (M+H).

Method 2 N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine

To a 0° C. solution ofN-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine(1.10 g, 2.04 mmol)) in MeOH (20 ml) was added in small portions NaBH₄(0.154 g, 4.07 mmol). The reaction was then allowed to reach roomtemperature. After 5 minutes full conversion to the correspondingalcohol was obtained: The reaction was quenched by the addition of 0.1MNH₄OAc buffer (3 ml) followed by concentration of the reaction mixture.The crude two diastereomeric alcohols (epimeric at the benzylic alcoholposition) were separated through preparative HPLC using an eluent of20-35% CH₃CN in 0.1M NH₄OAc buffer. The first eluting fraction wascollected and freeze dried. This yielded the desired diastereomer (0.40g, 36%) as a colourless solid. 1H NMR analysis confirmed that thisdiastereomer was of >95:5 dr. m/z: 541.5 (M−1). ¹H NMR [(CD₃)₂SO), 400MHz] δ 2.90 (d, 2H), 3.78 (d, 2H), 4.25 (d, 1H), 4.52 (s, 2H), 4.67-4.73(m, 1H), 5.06 (d, 1H), 6.97-7.38 (m, 12H), 8.35 (t, 1H).

Method 3 β,β-dimethyl-D-phenylalanine trifluoroacetate salt

Commercially availableN-(tert-butoxycarbonyl)-β,β-dimethyl-D-phenylalanine-2-methylpropan-2-aminesalt (1:1) (1.0 g, 2.73 mmol) was dissolved in CH₂Cl₂ (50 ml) followedby the addition of 1M HCl (aq. 100 ml). The aqueous phase was extractedwith CH₂Cl₂ (50 ml). The pooled organic phase was dried (MgSO₄) andconcentrated. To the residue was added CH₂Cl₂ (4 ml) and TFA (3 ml).After 2 h, the reaction mixture was concentrated to give the desiredcompound (0.83 g, 99%) as a colourless solid. ¹H NMR (D₂O, 400 MHz) δ1.38 (s, 3H), 1.45 (s, 3H), 4.17 (s, 1H), 7.26-7.42 (m, 5H).

Examples of Intermediates of Formula (VI) Method 4N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-alanine

N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-alaninewas dissolved in methanol (1.5 ml) whereafter sodium borohydride wasadded and the mixture was stirred for 30 minutes. After addition ofammonium acetate/H2O solution (2 ml), the methanol was evaporated andthe product purified by preparative HPLC (CH3CN/0.1% ammoniumacetate20:80-100:0). The fractions containing product confirmed by LC-MS werelyophilized and 27 mg (48%) of the desired product was obtained. m/z:555.0 (M−1).

Method 5N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-hydroxyethyl]thio)-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-tryptophan

To a solution of[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]aceticacid (0.050 g, 0.103 mmol) in CH₂Cl₂ (5 ml) was added Tryphtophanetert-butyl ester hydrochloride (0.037 g, 0.12 mmol) andN-Methylmorpholine (31 mg, 0.31 mmol) at room temperature under anatmosphere of nitrogen. After 10 minutes TBTU (43 mg, 0.13 mmol) wasadded. After 2 hours HPLC showed a 90% conversion and after 4 hours fullconversion was obtained to the corresponding tert-butyl-ester. The crudeester was put on a short pad of silica gel and eluted with EtOAc/CH₂Cl₂,25/75. Pure fractions were collected and concentrated. CH₂Cl₂ (5 ml) andTFA (1 ml) were added and the reaction was allowed to stir at roomtemperature for 4 hours. The resulting acid was concentrated and theremaining trace of TFA was azeotropically removed through co-evaporationwith toluene (2×5 ml). To the residue was added 5 ml of MeOH followed bythe addition of Sodium borohydride (0.016 g, 0.414 mmol). Fullconversion to the corresponding alcohol was achieved after 5 minutesaccording to HPLC analysis. The reaction was quenched by the addition of0.1M NH₄OAc buffer (1 ml). The volatiles were evaporated and the residuewas purified through preparative HPLC (gradient 20-50% CH₃CN in 0.1Mammonium acetate buffer). Freeze drying of pure fractions afforded thedesired product as a colourless solid (0.040 g, 58%). m/z: 670.3 (M−1).¹H NMR [(CD₃)₂SO), 400 MHz] δ 2.85-2.95 (m, 2H), 3.07-3.12 (m, 1H),3.22-3.27 (m, 1H), 4.24-4.27 (m, 1H), 4.34-4.38 (m, 1H), 4.41 (s, 2H),4.70-4.76 (m, 1H), 5.01-5.04 (m, 1H), 6.80-7.35 (m, 16H), 7.50-7.53 (m,1H), 7.85-7.92 (m, 1H), 10.76 (s, 1H).

Method 7N²-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine

[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]aceticacid (50 mg, 0.103 mmol), tert-butyl L-glutaminate hydrochloride (30 mg,0.124 mmol) and N-methylmorpholine (40 mg, 0.396 mmol) were dissolved inmethylene chloride (1 ml). TBTU (40 mg, 0.125 mmol) was added and themixture was stirred for 90 min at room temperature. The solvent wasevaporated and the residue was dissolved in formic acid (1 ml). Themixture was heated to 45-50° C. and stirred at this temperature for 4 h.The reaction mixture was evaporated under reduced pressure. Toluene (5ml) was added and evaporated. The residue was dissolved in methanol (1ml). NaBH4 (30 mg, 0.793 mmol) was added and the mixture was stirred for15 min at room temperature. Acetic acid (50 mg, 0.83 mmol) was added andthe reaction mixture was evaporated under reduced pressure. The residuewas purified by preparative HPLC using acetonitrile/ammonium acetatebuffer (35:65) as eluent. After freeze-drying 47 mg (74%) of the titlecompound was obtained. ¹H-NMR, 300 MHz, DMSO): 1.72-2.16 (m, 4H),2.81-2.95 (m, 2H), 4.08-4.20 (m, 1H), 4.26-4.31 (m, 1H), 4.50 (s, 2H),4.65-4.78 (m, 1H), 5.03-5.08 (m, 1H), 6.68 (s, 1H), 6.89-7.44 (m, 14H),8.29 (d, 1H).

Method 8N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-serine

A solution of[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]aceticacid (0.050 g, 0.103 mmol), O-(tert-butyl)-D-Serine tert-butyl esterhydrochloride (0.032 g, 0.147 mmol) and N-Methylmorpholine (0.035 ml,0.318 mmol) in DCM (4 ml) was stirred at RT for 5 min, after which TBTU(0.044 g, 0.137 mmol) was added. After 3 h, the conversion to the ester(m/z: 683.1) was completed and the solution was added TFA (2 ml). After22 h, the solvent was removed under reduced pressure and the residue(m/z: 571.1) was dissolved in MeOH (4 ml). To the solution weresuccessively added small portions of NaBH4 (totally 0.130 g, 3.44 mmol)until the reduction was completed. The reaction mixture was added a 0.1Mammonium acetate buffer (3 ml) and the methanol was removed underreduced pressure. The remaining solution was purified by preparativeHPLC using a gradient of 20-60% MeCN in 0.1M ammonium acetate buffer aseluent. After freeze-drying, 0.021 g (36% yield) of the desired product(as a mixture of diastereomers) was obtained as a white solid. M/z:573.1. ¹H NMR (DMSO, 400 MHz): δ 2.84-2.96 (m, 2H), 3.47 (dd, 1H), 3.69(dd, 1H), 3.97-4.06 (m, 1H), 4.27-4.32 (m, 1H), 4.52 (ABq, 2H),4.68-4.77 (m, 1H), 5.04-5.09 (m, 1H), 5.65 (bs, 1H), 6.99 (d, 2H),7.07-7.41 (m, 10H), 7.89 (d, 1H).

Method 9 N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-N⁶-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-lysine

A mixture of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or8)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine(0.0093 g, 0.017 mmole), N-methylmorpholin (0.010 mL, 0.051 mmole) inDMF (1 mL) was stirred, TBTU (0.0077 g, 0.025 mmole) was added. Themixture was stirred for 50 minutes under N₂-atmosphere.N⁶-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-lysine (0.010 g, 0.025 mmole)was added and stirred for 1 hour. A small amount of water was added andthe solvent was removed under reduced pressure. The residue was purifiedby preparative HPLC on a Kromasil C8-column using a gradient of 5-100%MeCN in 0.1M ammonium acid buffer as eluent. After removing the solventunder reduced pressure and freeze-drying from water, 0.010 g (65%) ofthe desired product was obtained.

M/z 893.35

Absorption

Absorption of the compounds of formula (I) was tested in a Caco-2 cellsmodel (Gastroenterology 1989, 96, 736):

Caco value Compound (I) (10⁻⁶ cm/sec)N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R)-2- 0.02(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3- methyl-D-valineN-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R)-2- 0.04(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3- cyclohexyl-D-alanine

1. A single diastereomeric compound of formula (I)

wherein: R¹ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein saidC₁₋₆alkyl may be optionally substituted by one or more hydroxy, amino,guanidino, carbamoyl, carboxy, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁-C₆alkylcarbonylamino, C₁₋₆alkylS(O)_(a)wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and wherein any aryl group maybe optionally substituted by one or two substituents selected from halo,hydroxy, C₁₋₆alkyl and C₁₋₆alkoxy; R² is hydrogen, a branched orunbranched C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein said C₁₋₆alkyl maybe optionally substituted by one or more hydroxy, amino, guanidino,carbamoyl, carboxy, C₁₋₆alkoxy, (C₁-C₄ alkyl)₃Si, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0-2,C₃₋₆cycloalkyl or aryl; and wherein any aryl group may be optionallysubstituted by one or two substituents selected from halo, hydroxy,C₁₋₆alkyl and C₁₋₆alkoxy; R³ is hydrogen, alkyl, halo or C₁₋₆alkoxy; R⁴is hydrogen, halo or C₁₋₆alkoxy; R⁵ is hydrogen, C₁₋₆ alkyl, arylalkyl,or arylC₁₋₆ alkyl; R⁶ is hydrogen, C₁₋₆ alkyl, or arylC₁₋₆ alkyl;wherein R⁵ and R² may form a ring with 2-7 carbon atoms and wherein R⁶and R² may form a ring with 3-6 carbon atoms; or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.2. A compound according to claim 1, wherein: R¹ is hydrogen.
 3. Acompound according to claim 1, wherein: R² is hydrogen, a branched orunbranched C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein said C₁₋₆alkyl maybe optionally substituted by one or more hydroxy, amino, acylamino,C₁₋₆alkylS(O)_(a) wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and whereinany aryl group may be optionally substituted by hydroxy.
 4. A compoundaccording to claim 1, wherein: R³ is hydrogen, alkyl, halo or methoxy.5. A compound according to claim 1, wherein: R³ is hydrogen, methyl,chlorine, fluorine or methoxy.
 6. A compound according to claim 1,wherein: R⁴ is halo.
 7. A compound according to claim 1, wherein: R⁴ ischlorine or fluorine.
 8. A compound according to claim 1, wherein: R⁶ ishydrogen, arylC₁₋₆ or R⁶ and R² form a ring with 3-6 carbon atoms.
 9. Acompound according to claim 1, wherein: R¹ is hydrogen; R² is a branchedor unbranched C₁₋₄alkyl, optionally substituted by a C₃₋₆cycloalkyl oran amino; R³ and R⁴ are halo; R⁵ is hydrogen or C₁₋₆ alkyl; and R⁶ ishydrogen.
 10. One or more compounds selected from:N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valine;1-[(N-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[(2R orS)-2-(4-chlorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]cyclopropanecarboxylicacid; N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-methyl-D-valine;N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-cyclohexyl-D-alanine;N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-β,β-dimethyl-D-phenylalanine; andN-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R orS)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine.11. A pharmaceutical formulation comprising a compound according toclaim 1 in admixture with a pharmaceutically acceptable adjuvant,diluent and/or carrier.
 12. A combination of a compound according toformula (I)

wherein: R¹ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein saidC₁₋₆alkyl may be optionally substituted by one or more hydroxy, amino,guanidino, carbamoyl, carboxy, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁-C₆alkylcarbonylamino, C₁₋₆alkylS(O)_(a)wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and wherein any aryl group maybe optionally substituted by one or two substituents selected from halo,hydroxy, C₁₋₆alkyl, and C₁₋₆alkoxy; R² is hydrogen, a branched orunbranched C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein said C₁₋₆alkyl maybe optionally substituted by one or more hydroxy, amino, guanidino,carbamoyl, carboxy, C₁₋₆alkoxy, (C₁-C₄ alkyl)₃Si, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0-2,C₃₋₆cycloalkyl or aryl; and wherein any aryl group may be optionallysubstituted by one or two substituents selected from halo, hydroxy,C₁₋₆alkyl, and C₁₋₆alkoxy; R³ is hydrogen, alkyl, halo or C₁₋₆alkoxy; R⁴is hydrogen, halo or C₁₋₆alkoxy; R⁵ is hydrogen, C₁₋₆ alkyl, arylalkyl,or arylC₁₋₆ alkyl; R⁶ is hydrogen, C₁₋₆ alkyl, or arylC₁₋₆ alkyl;wherein R⁵ and R² may form a ring with 2-7 carbon atoms and wherein R⁶and R² may form a ring with 3-6 carbon atoms; with a PPAR alpha and/orgamma agonist.
 13. A combination of a compound according to formula (I)

wherein: R¹ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein saidC₁₋₆alkyl may be optionally substituted by one or more hydroxy, amino,guanidino, carbamoyl, carboxy, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁-C₆alkylcarbonylamino, C₁₋₆alkylS(O)_(a)wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and wherein any aryl group maybe optionally substituted by one or two substituents selected from halo,hydroxy, C₁₋₆alkyl, and C₁₋₆alkoxy; R² is hydrogen, a branched orunbranched C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein said C₁₋₆alkyl maybe optionally substituted by one or more hydroxy, amino, guanidino,carbamoyl, carboxy, C₁₋₆alkoxy, (C₁-C₄ alkyl)₃Si, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0-2,C₃₋₆cycloalkyl or aryl; and wherein any aryl group may be optionallysubstituted by one or two substituents selected from halo, hydroxy,C₁₋₆alkyl, and C₁₋₆alkoxy; R³ is hydrogen, alkyl, halo or C₁₋₆alkoxy; R⁴is hydrogen, halo or C₁₋₆alkoxy; R⁵ is hydrogen, C₁₋₆ alkyl, arylalkyl,or arylC₁₋₆ alkyl; R⁶ is hydrogen, C₁₋₆ alkyl, or arylC₁₋₆ alkyl;wherein R⁵ and R² may form a ring with 2-7 carbon atoms and wherein R⁶and R² may form a ring with 3-6 carbon atoms; with an HMG Co-A reductaseinhibitor.
 14. A process for preparing a compound of formula (I)

wherein: R¹ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein saidC₁₋₆alkyl may be optionally substituted by one or more hydroxy, amino,guanidino, carbamoyl, carboxy, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁-C₆alkylcarbonylamino, C₁₋₆alkylS(O)_(a)wherein a is 0-2, C₃₋₆cycloalkyl or aryl; and wherein any aryl group maybe optionally substituted by one or two substituents selected from halo,hydroxy, C₁₋₆alkyl, and C₁₋₆alkoxy; R² is hydrogen, a branched orunbranched C₁₋₆alkyl, C₃₋₆cycloalkyl or aryl; wherein said C₁₋₆alkyl maybe optionally substituted by one or more hydroxy, amino, guanidino,carbamoyl, carboxy, C₁₋₆alkoxy, (C₁-C₄ alkyl)₃Si, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0-2,C₃₋₆cycloalkyl or aryl; and wherein any aryl group may be optionallysubstituted by one or two substituents selected from halo, hydroxy,C₁₋₆alkyl, and C₁₋₆alkoxy; R³ is hydrogen, alkyl, halo or C₁₋₆alkoxy; R⁴is hydrogen, halo or C₁₋₆alkoxy; R⁵ is hydrogen, C₁₋₆ alkyl, arylalkyl,or arylC₁₋₆ alkyl; R⁶ is hydrogen, C₁₋₆alkyl, or arylC₁₋₆ alkyl; whereinR⁵ and R² may form a ring with 2-7 carbon atoms and wherein R⁶ and R²may form a ring with 3-6 carbon atoms; or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof which processcomprises: Process 1) reacting a compound of formula (II):

wherein R³ and R⁴ are as defined above, with a compound of formula(III):

wherein L is a displaceable group, and wherein R¹ and R² are as definedabove; or Process 2) reacting an acid of formula (IV):

or an activated derivative thereof, wherein R³ and R⁴ are as definedabove; with an amine of formula (V):

wherein R¹ and R² are as defined above; or Process 3): reacting an acidof formula (VI):

or an activated derivative thereof, wherein R¹, R³, and R⁴ are asdefined above with an amine of formula (VII):

wherein R² is as defined above; or Process 4): reducing a compound offormula (VIII):

wherein R¹, R², R³, and R⁴ are as defined above; or Process 5): reactinga compound of formula (IX):

wherein R¹, R², and R⁴ are as defined above; with a compound of formula(X):

wherein L is a displaceable group and R³ is as defined above; or Process6): reacting a compound of formula (XI):

wherein L is a displaceable group, and R¹, R², and R⁴ are as definedabove; with a compound of formula (XII):

wherein R³ is as defined above; or Process 7): De-esterifying a compoundof formula (XIII)

wherein R¹, R², R³, and R⁴ are as defined above; and wherein the groupC(O)OR is an ester group.